Characterizing a Raphe Chemosensory Amplifier. Project summary: Knowledge of the neurons with which the brain detects and responds to changes in CO2/pH (central chemosensitivity) is critical to understanding both homeostatic regulation and the nature of diseases resulting from failures in chemosensitivity, such as sleep apnea, Congenital Central Hypoventilation Syndrome and the Sudden Infant Death Syndrome. Medullary raph neurons synthesizing the neurotransmitter serotonin (5HT) or aminobutyric acid (GABA) are proposed as 1st order chemosensory neurons. Unknown, however, are the identities and characteristics of 2nd order chemosensory neurons, responsible for integrating, amplifying and coordinating the activities of 1st order neurons, to modulate homeostatic reflex responses to chemosensory stimuli. We postulate that 1st order raph 5HT and GABA chemosensory neurons reciprocally interact and drive a specific population of 2nd order neurons which, together, form a local raph chemosensory amplifier (RCA) network. Our overarching hypothesis is that 1st order chemosensory neurons of the medullary raph interact, and integrate with a population of raph 2nd order neurons, to form a local network which provides coordinated output to respiratory control centers. To test this hypothesis we have two aims, to demonstrate; Specific Aim 1: Intrinsic sensitivity of raph 5HT and GABA neurons is shaped by the RCA network. Specific Aim 2: RCAI integrate and amplify inputs from 1st order 5HT and/or GABA neurons. Proposed studies will determine the neuron phenotypes of previously uncharacterized but critical 2nd order chemosensory neurons within the raph. As such, studies will document a basic cellular network necessary for central chemosensitivity. Results will suggest an organization of the raph chemosensory system and advance the understanding of central chemoreception by contributing definitive information about the neurons and network mechanisms involved in this vital process.